Rheumatoid arthritis (RA) is a complex inflammatory disorder causing synovitis and joint destruction. Combinatorial use of disease-modifying anti-rheumatic drugs (DMARDs) as well as the advent of biologic agents has revolutionized therapeutic outcomes in RA. However, 40-50% of patients are refractory to any given therapy. The underlying immune mechanisms that define and predict clinical outcome remain unclear. In part, this is due to the paucity of data on pathways that are activated in the joint of patients at different stages of RA. The University of Pittsburgh has developed a strong collaborative team of clinicians and basic and translational scientists that is uniquely positioned to answer this nee through the Accelerated Medicines Partnership. Specifically, we offer a large cohort of RA patients under care of a single network of Pittsburgh rheumatologists; proven experience in recruiting patients for clinical registries and studies with accompanying sample banking: around one-quarter of our RA cohort are already enrolled in our active, NIH-funded research registry (RACER) through which clinical disease activity, labs, and blood are collected at each clinic visit; a state-of-the-art clinical data management and specimen tracking system; established collaborations to provide surgical samples (orthopaedics, IRB-approved), as well as ultrasound (US)-guided biopsies to be performed by specialists in this technique (IRB in process); expertise in tissue processing to isolate lymphocytes for advanced immune cell analytics; expertise in RNA-Seq, including analysis of human tissues (fresh and formalin-fixed) as well as bioinformatics; established workflow to perform all stages efficiently and rapidly at a single site to optimize data quality and integrity of these valuable samples. In UH2 Research Phase 0, we will establish standardized methods and feasibility parameters for tissue collection, processing, and analysis. Initially we will make use of readily-available synovial tissues from standard orthopaedic procedures such as joint replacement and synovectomy, and then validate these procedures on ultrasound-guided biopsy samples. In UH2 Research Phase I, we will then apply the standardized procedures developed in Phase 0 to determine heterogeneity between patient samples, compare RA versus OA and source of cells (blood vs. tissue, surgery vs. biopsy). These parameters will allow accurate power analysis to determine numbers of patients and types of analyses that are required for Phase II. In UH3 Research Phase II, we propose a controlled clinical study in which RA patients with active disease that have not responded to standard first-line therapy with methotrexate or TNF inhibitor will be randomized to receive biologic therapy. Joint biopsy and blood will be analyzed in relation to clinical outcome, and systems biology applied to determine causal pathway activation in relation to disease activity and therapy response. We also expect to participate in in-vitro and in-vivo validation studies based on pathways identified in Phase I, as well as emerging pilot project data.